1. Field of the Invention
This invention relates to device and apparatus for processing biomolecule arrays, and in particular, to an “array of arrays” microplate and an automated processing system. The invention is applicable to DNA diagnostics, mutation screening, gene expression monitoring, protein analysis, cell-based assays and other applications using a robotics workstation.
2. Description of the Related Art
Microarrays such as DNA, oligo, and protein microarrays are becoming a standard tool for monitoring changes in gene expression. This technique has found rapidly growing use in many molecular biology laboratories. A variety of structural and functional genomic characteristics can be studied in addition to expression or transcription. In a Microarrays assay from hundreds to tens of thousands of probes are attached to a substrate in an array form, and sample solutions are incubated on these arrays. By using known sequence of the probe (oligo or cDNA) at each spot on the array, the specificity inherent in hybridization gives indication as to which genes are present in the sample. Many samples are often needed to track the progress of a disease, or to identify genetic variation across hundreds of people. This requires a careful comparison of data of different arrays.
Currently, the majority of DNA arrays are formed on glass microscope slides. In a typical process. A robotic “spotter” is used to deposit small amounts of fluids, containing the probes onto a glass slide to form an array. Approximately 10,000 spots can be arrayed onto a glass slide. Next, a solution of targets is applied on the slide, typically by hand. After the slide is then placed in an incubator/mixer for several hours the fluorescent signals from the bound targets are imaged using a laser and a photomultiplier tube. This method, however, suffers from low throughput and poor data quality and reproducibility.
An alternative to using glass slides would be to use existing molded polymer titer plates, where arrays or printed into the wells. The microtiter plate is a well-known tool; the attachment of biomolecules within the microwell either as single elements (e.g., ELISA plates) or in the form of arrays (e.g., Genometrix, WO 98/29736) is also well known. The reading of arrays, however, is difficult in conventional microwells without the use of expensive equipment. There are also limitations in terms of field of focus and uniform lighting of the bottom of the well using conventional microtiter plates. In addition, the non-symmetrical design of these plates (solid bottom with open topped wells) results in molded parts that warp due to differential thermal expansion. As a result, conventional molded titer plates often fail to meet flatness criterion required for array applications. For example, for accurate dispensing of nanoliter amounts of fluids using pin printers, it is critical that the substrate is flat within 10% of the vertical travel of the pin. If the vertical travel is 0.06 inches, then the flatness must be within 0.006 inches, which is often difficult to meet by molded titer plates. Further, when the plates are heated, warp also creates variable air gaps between the wells and the heating fixture on which the plate is placed. These air gaps lead to variable thermal resistance from well to well, which leads to difficulties in controlling incubation or hybridization temperature from one array to another.